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1.
Adv Exp Med Biol ; 1310: 509-531, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33834448

RESUMEN

Metabolomics is the systematic study of metabolite profiles of complex biological systems, and involves the systematic identification and quantification of metabolites. Metabolism is integrated with all biochemical reactions in biological systems; thus metabolite profiles provide collective information on biochemical processes induced by genetic or environmental perturbations. Transcriptomes or proteomes may not be functionally active and not always reflect phenotypic variations. The metabolome, however, consists of the biomolecules closest to the phenotype of living organisms, and is often called the molecular phenotype of biological systems. Thus, metabolome alterations can easily result in disease states, providing important clues to understand pathophysiological mechanisms contributing to various biomedical symptoms. The metabolome and metabolomics have been emphasized in translational research related to biomarker discovery, drug target discovery, drug responses, and disease mechanisms. This review describes the basic concepts, workflows, and applications of mass spectrometry-based metabolomics in translational research.


Asunto(s)
Metabolómica , Investigación en Medicina Traslacional , Espectrometría de Masas , Metaboloma , Fenotipo
2.
J Transl Med ; 19(1): 132, 2021 03 31.
Artículo en Inglés | MEDLINE | ID: mdl-33789686

RESUMEN

Coronavirus disease 2019 (COVID-19) global pandemic has created unique challenges to healthcare systems throughout the world. Ensuring subjects' safety is mandatory especially in oncology, in consideration of cancer patients' particular frailty. We examined the proportion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgM and/or IgG positive subjects in three different groups from Istituto Nazionale Tumori - IRCCS "Fondazione G. Pascale" in Naples (Campania region, Italy): cancer patients treated with Innovative Immunotherapy (Immune Checkpoint Inhibitors, ICIs), cancer patients undergoing standard Chemotherapies (CHTs) and healthcare providers. 9 out of 287 (3.1%) ICIs patients resulted positive, with a significant lower percentage in respect to CHTs patients (39 positive subjects out of 598, 6.5%) (p = 0.04). There was no statistically significant difference between ICIs cohort and healthcare providers, 48 out of 1050 resulting positive (4.6%). Performing a Propensity Score Matching based on gender and tumor stage, the effect of treatment on seropositivity was analyzed through a regression logistic model and the ICIs treatment resulted to be the only protective factor significantly (p = 0.03) associated with positivity (odds ratio-OR: 0.41; 95% confidence interval-CI 0.18-0.91). According to these preliminary data, ICIs would appear to be a protective factor against the onset of COVID-19 infection.


Asunto(s)
/prevención & control , Inmunoterapia , Neoplasias/terapia , Anciano , Anticuerpos Antivirales/sangre , Antineoplásicos/uso terapéutico , /inmunología , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Italia/epidemiología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Neoplasias/complicaciones , Neoplasias/inmunología , Pandemias , Estudios Retrospectivos , Investigación en Medicina Traslacional
3.
Int J Nanomedicine ; 16: 2087-2106, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33727815

RESUMEN

Nanotechnology has substantially progressed in the past decades, giving rise to numerous possible applications in different biomedical fields. In particular, the use of nanoparticles in endodontics has generated significant interest due to their unique characteristics. As a result of their nanoscale dimensions, nanoparticles possess several properties that may enhance the treatment of endodontic infections, such as heightened antibacterial activity, increased reactivity and the capacity to be functionalized with other reactive compounds. Effective disinfection and sealing of the root canal system are the hallmarks for successful endodontic treatment. However, the presence of bacterial biofilms and resistance to endodontic disinfectants pose a significant challenge to this goal. This has encouraged the investigation of antibacterial nanoparticle-based irrigants and intracanal medicaments, which may improve the elimination of endodontic infections. In addition, photosynthesizer-functionalized nanoparticles could also serve as a worthy adjunct to root canal disinfection strategies. Furthermore, despite the myriad of commercially available options for endodontic obturation, the "ideal" material has yet to be conceived. This has led to the development of various experimental nanoparticle-incorporated obturation materials and sealers that exhibit a range of favourable physicochemical properties including enhanced antibacterial efficacy and bioactivity. Nanoparticle applications also show promise in the field of regenerative endodontics, such as supporting the release of bioactive molecules and enhancing the biophysical properties of scaffolds. Given the constantly growing body of research in this field, this article aims to present an overview of the current evidence pertaining to the potential translational applications of nanoparticles in endodontics.


Asunto(s)
Endodoncia , Nanopartículas/uso terapéutico , Investigación en Medicina Traslacional , Humanos , Nanopartículas/efectos adversos , Fotoquimioterapia , Medicina Regenerativa , Tratamiento del Conducto Radicular
4.
Cell Transplant ; 30: 963689721995455, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33650894

RESUMEN

During the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many critically ill patients died of severe pneumonia, acute respiratory distress syndrome (ARDS), or multiple organ dysfunction syndrome. To date, no specific treatments have been proven to be effective for coronavirus disease 2019 (COVID-19). In the animal models and clinical applications, mesenchymal stromal/stem cells (MSCs) have been shown safety and efficacy for the treatment of respiratory virus infection through their abilities of differentiation and immunomodulation. Besides, possessing several advantages of MSC-derived extracellular vesicles (EVs) over MSCs, EV-based therapy also holds potential therapeutic effects in respiratory virus infection. In this review, we summarized the basic characteristics and mechanisms of COVID-19 and MSCs, outlined some preclinical and clinical studies of MSCs or MSC-EVs for respiratory virus infection such as influenza virus and SARS-CoV-2, shed light on the common problems that we should overcome to translate MSC therapy into clinical application, and discussed some safe issues related to the use of MSCs.


Asunto(s)
/terapia , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Animales , Ensayos Clínicos como Asunto , Exosomas , Vesículas Extracelulares , Humanos , Seguridad del Paciente , Investigación en Medicina Traslacional
5.
J Transl Med ; 19(1): 129, 2021 03 30.
Artículo en Inglés | MEDLINE | ID: mdl-33785043

RESUMEN

BACKGROUND: Coronavirus disease (COVID-19) pandemic has affected health and lifestyle behaviors of people globally. This project aims to identify the impact of COVID-19 on lifestyle behavior of individuals in the Middle East and North Africa (MENA) region during confinement. METHODS: We conducted an online survey in 17 countries (Egypt, Jordan, United Arab Emirates, Kuwait, Bahrain, Saudi Arabia, Oman, Qatar, Yemen, Syria, Palestine, Algeria, Morocco, Libya, Tunisia, Iraq, and Sudan) from the MENA region on August and September 2020. The questionnaire included self-reported information on lifestyle behaviors, including physical activity, eating habits, smoking, watching television, social media use and sleep before and during the pandemic. Logistic regression was performed to analyze the impact of COVID-19 on lifestyle behaviors. RESULTS: A total of 5896 participants were included in the final analysis and 62.8% were females. The BMI of the participants was 25.4 ± 5.8 kg/m2. Around 38.4% of the participants stopped practicing any physical activities during the confinement (P < 0.001), and 57.1% reported spending more than 2 h on social media (P < 0.001). There were no significant changes in smoking habits. Also, 30.9% reported an improvement in their eating habits compared with 24.8% reported worsening of their eating habits. Fast-food consumption decreased significantly in 48.8% of the study population. This direct/indirect exposure to COVID-19 was associated with an increased consumption of carbohydrates (OR = 1.09; 95% CI = 1.02-1.17; P = 0.01), egg (OR = 1.08; 95% CI = 1.02-1.16; P = 0.01), sugar (OR = 1.09; 95% CI = 1.02-1.16; P = 0.02), meat, and poultry (OR = 1.13; 95% CI = 1.06-1.20; P < 0.01). There was also associated increase in hours spent on watching television (OR = 1.07; 95% CI = 1.02-1.12; P < 0.01) and social media (OR = 1.09; 95% CI = 1.01-1.18; P = 0.03). However, our results showed a reduction in sleeping hours among those exposed to COVID-19 infection (OR = 0.85; 95% CI = 0.77-0.94; P < 0.01). CONCLUSIONS: The COVID-19 pandemic was associated with an increase in food consumption and sedentary life. Being exposed to COVID-19 by direct infection or through an infected household is a significant predictor of amplifying these changes. Public health interventions are needed to address healthy lifestyle behaviors during and after the COVID-19 pandemic.


Asunto(s)
/epidemiología , Conductas Relacionadas con la Salud , Estilo de Vida , Pandemias , Adolescente , Adulto , África del Norte/epidemiología , Niño , Estudios Transversales , Conducta Alimentaria , Femenino , Humanos , Masculino , Persona de Mediana Edad , Medio Oriente/epidemiología , Conducta Sedentaria , Encuestas y Cuestionarios , Investigación en Medicina Traslacional , Adulto Joven
6.
Curr Opin Pulm Med ; 27(3): 155-162, 2021 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-33654014

RESUMEN

PURPOSE OF REVIEW: COVID-19 has put the in-vitro-diagnostic community under an unprecedented spotlight, with a global requirement for accurate SARS-CoV-2 tests. This review will outline technological responses to this need and the analytical considerations required for their translation to routine use. RECENT FINDINGS: SARS-CoV-2 diagnostic solutions directly detect the virus or measure host-derived surrogate markers of infection. With pressure upon supply chains for the 'traditional' molecular approaches, a wide variety of analytical tools spanning the molecular, serology, imaging and chemistry space are being developed, including high throughput solutions and simplified near-patient formats. SUMMARY: The unique genetic nature of SARS-CoV-2 means high analytical specificity is achievable by most diagnostic formats. However, clinical sensitivity assessment is complicated by wide discrepancies in analytical range and challenges associated with standardising these differences. When coupled with the acute nature of SARS-CoV-2 infection, reported precise metrics of test performance must be questioned. The response to SARS-CoV-2 has delivered considerable diagnostic innovation, but for a technology to be maximised, it must be demonstrably reproducible and fit for purpose. If novel diagnostic solutions for SARS-CoV-2 are to succeed, equally innovative mechanisms are needed to ensure widespread clinical and surveillance application, enabling agreed standards and metrics to ensure comparability.


Asunto(s)
/métodos , Invenciones , /virología , Humanos , /aislamiento & purificación , Sensibilidad y Especificidad , Investigación en Medicina Traslacional
8.
Sci Transl Med ; 13(583)2021 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-33658355

RESUMEN

Seasonal influenza vaccines confer protection against specific viral strains but have restricted breadth that limits their protective efficacy. The H1 and H3 subtypes of influenza A virus cause most of the seasonal epidemics observed in humans and are the major drivers of influenza A virus-associated mortality. The consequences of pandemic spread of COVID-19 underscore the public health importance of prospective vaccine development. Here, we show that headless hemagglutinin (HA) stabilized-stem immunogens presented on ferritin nanoparticles elicit broadly neutralizing antibody (bnAb) responses to diverse H1 and H3 viruses in nonhuman primates (NHPs) when delivered with a squalene-based oil-in-water emulsion adjuvant, AF03. The neutralization potency and breadth of antibodies isolated from NHPs were comparable to human bnAbs and extended to mismatched heterosubtypic influenza viruses. Although NHPs lack the immunoglobulin germline VH1-69 residues associated with the most prevalent human stem-directed bnAbs, other gene families compensated to generate bnAbs. Isolation and structural analyses of vaccine-induced bnAbs revealed extensive interaction with the fusion peptide on the HA stem, which is essential for viral entry. Antibodies elicited by these headless HA stabilized-stem vaccines neutralized diverse H1 and H3 influenza viruses and shared a mode of recognition analogous to human bnAbs, suggesting that these vaccines have the potential to confer broadly protective immunity against diverse viruses responsible for seasonal and pandemic influenza infections in humans.


Asunto(s)
Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Vacunas contra la Influenza/inmunología , Primates/inmunología , Animales , Anticuerpos Antivirales/biosíntesis , Anticuerpos Antivirales/química , Complejo Antígeno-Anticuerpo/química , Anticuerpos ampliamente neutralizantes/biosíntesis , Anticuerpos ampliamente neutralizantes/química , Ferritinas/química , Ferritinas/inmunología , Glicoproteínas Hemaglutininas del Virus de la Influenza/química , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Humanos , Vacunas contra la Influenza/administración & dosificación , Vacunas contra la Influenza/química , Gripe Humana/inmunología , Gripe Humana/virología , Macaca fascicularis , Modelos Moleculares , Nanopartículas/química , Pandemias , Primates/virología , Estructura Cuaternaria de Proteína , Investigación en Medicina Traslacional
10.
Toxicol Appl Pharmacol ; 416: 115444, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33549591

RESUMEN

Health disparities exist dependent on socioeconomic status, living conditions, race/ethnicity, diet, and exposures to environmental pollutants. Herein, the various exposures contributing to a person's exposome are collectively considered social determinants of health (SDOH), and the SDOH-exposome impacts health more than health care. This review discusses the extent of evidence of the physiologic consequences of these exposures at the intracellular level. We consider how the SDOH-exposome, which captures how individuals live, work and age, induces cell processes that modulate a conceptual "redox rheostat." Like an electrical resistor, the SDOH-exposome, along with genetic predisposition and age, regulate reductive and oxidative (redox) stress circuits and thereby stimulate inflammation. Regardless of the source of the SDOH-exposome that induces chronic inflammation and immunosenescence, the outcome influences cardiometabolic diseases, cancers, infections, sepsis, neurodegeneration and autoimmune diseases. The endogenous redox rheostat is connected with regulatory molecules such as NAD+/NADH and SIRT1 that drive redox pathways. In addition to these intracellular and mitochondrial processes, we discuss how the SDOH-exposome can influence the balance between metabolism and regulation of immune responsiveness involving the two main molecular drivers of inflammation, the NLRP3 inflammasome and NF-κB induction. Mitochondrial and inflammasome activities play key roles in mediating defenses against pathogens and controlling inflammation before diverse cell death pathways are induced. Specifically, pyroptosis, cell death by inflammation, is intimately associated with common disease outcomes that are influenced by the SDOH-exposome. Redox influences on immunometabolism including protein cysteines and ion fluxes are discussed regarding health outcomes. In summary, this review presents a translational research perspective, with evidence from in vitro and in vivo models as well as clinical and epidemiological studies, to outline the intracellular consequences of the SDOH-exposome that drive health disparities in patients and populations. The relevance of this conceptual and theoretical model considering the SARS-CoV-2 pandemic are highlighted. Finally, the case of asthma is presented as a chronic condition that is modified by adverse SDOH exposures and is manifested through the dysregulation of immune cell redox regulatory processes we highlight in this review.


Asunto(s)
Disparidades en el Estado de Salud , Mediadores de Inflamación/metabolismo , Líquido Intracelular/metabolismo , Estrés Oxidativo/fisiología , Determinantes Sociales de la Salud/tendencias , Contaminantes Ambientales/efectos adversos , Contaminantes Ambientales/inmunología , Contaminantes Ambientales/metabolismo , Humanos , Mediadores de Inflamación/inmunología , Líquido Intracelular/inmunología , Investigación en Medicina Traslacional/métodos , Investigación en Medicina Traslacional/tendencias
11.
J Frailty Aging ; 10(2): 110-120, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33575699

RESUMEN

BACKGROUND: The Geroscience field focuses on the core biological mechanisms of aging, which are involved in the onset of age-related diseases, as well as declines in intrinsic capacity (IC) (body functions) leading to dependency. A better understanding on how to measure the true age of an individual or biological aging is an essential step that may lead to the definition of putative markers capable of predicting healthy aging. OBJECTIVES: The main objective of the INStitute for Prevention healthy agIng and medicine Rejuvenative (INSPIRE) Platform initiative is to build a program for Geroscience and healthy aging research going from animal models to humans and the health care system. The specific aim of the INSPIRE human translational cohort (INSPIRE-T cohort) is to gather clinical, digital and imaging data, and perform relevant and extensive biobanking to allow basic and translational research on humans. METHODS: The INSPIRE-T cohort consists in a population study comprising 1000 individuals in Toulouse and surrounding areas (France) of different ages (20 years or over - no upper limit for age) and functional capacity levels (from robustness to frailty, and even dependency) with follow-up over 10 years. Diversified data are collected annually in research facilities or at home according to standardized procedures. Between two annual visits, IC domains are monitored every 4-month by using the ICOPE Monitor app developed in collaboration with WHO. Once IC decline is confirmed, participants will have a clinical assessment and blood sampling to investigate markers of aging at the time IC declines are detected. Biospecimens include blood, urine, saliva, and dental plaque that are collected from all subjects at baseline and then, annually. Nasopharyngeal swabs and cutaneous surface samples are collected in a large subgroup of subjects every two years. Feces, hair bulb and skin biopsy are collected optionally at the baseline visit and will be performed again during the longitudinal follow up. EXPECTED RESULTS: Recruitment started on October 2019 and is expected to last for two years. Bio-resources collected and explored in the INSPIRE-T cohort will be available for academic and industry partners aiming to identify robust (set of) markers of aging, age-related diseases and IC evolution that could be pharmacologically or non-pharmacologically targetable. The INSPIRE-T will also aim to develop an integrative approach to explore the use of innovative technologies and a new, function and person-centered health care pathway that will promote a healthy aging.


Asunto(s)
Bancos de Muestras Biológicas , Geriatría , Envejecimiento Saludable , Investigación en Medicina Traslacional , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Francia , Humanos , Persona de Mediana Edad
13.
J Transl Med ; 19(1): 30, 2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-33413461

RESUMEN

BACKGROUND: COVID-19 has caused a global pandemic and the death toll is increasing. However, there is no definitive information regarding the type of clinical specimens that is the best for SARS-CoV-2 detection, the antibody levels in patients with different duration of disease, and the relationship between antibody level and viral load. METHODS: Nasopharyngeal swabs, anal swabs, saliva, blood, and urine specimens were collected from patients with a course of disease ranging from 7 to 69 days. Viral load in different specimen types was measured using droplet digital PCR (ddPCR). Meanwhile, anti-nucleocapsid protein (anti-N) IgM and IgG antibodies and anti-spike protein receptor-binding domain (anti-S-RBD) IgG antibody in all serum samples were tested using ELISA. RESULTS: The positive detection rate in nasopharyngeal swab was the highest (54.05%), followed by anal swab (24.32%), and the positive detection rate in saliva, blood, and urine was 16.22%, 10.81%, and 5.41%, respectively. However, some patients with negative nasopharyngeal swabs had other specimens tested positive. There was no significant correlation between antibody level and days after symptoms onset or viral load. CONCLUSIONS: Other specimens could be positive in patients with negative nasopharyngeal swabs, suggesting that for patients in the recovery period, specimens other than nasopharyngeal swabs should also be tested to avoid false negative results, and anal swabs are recommended. The antibody level had no correlation with days after symptoms onset or the viral load of nasopharyngeal swabs, suggesting that the antibody level may also be affected by other factors.


Asunto(s)
Anticuerpos Antivirales/sangre , /virología , /aislamiento & purificación , Carga Viral , Adulto , Anciano , Anciano de 80 o más Años , Canal Anal/virología , Sangre/virología , China/epidemiología , Reacciones Falso Negativas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nasofaringe/virología , Pandemias , Saliva/virología , Manejo de Especímenes , Factores de Tiempo , Investigación en Medicina Traslacional , Orina/virología
14.
J Transl Med ; 19(1): 29, 2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-33413480

RESUMEN

BACKGROUND: Limited data was available for rapid and accurate detection of COVID-19 using CT-based machine learning model. This study aimed to investigate the value of chest CT radiomics for diagnosing COVID-19 pneumonia compared with clinical model and COVID-19 reporting and data system (CO-RADS), and develop an open-source diagnostic tool with the constructed radiomics model. METHODS: This study enrolled 115 laboratory-confirmed COVID-19 and 435 non-COVID-19 pneumonia patients (training dataset, n = 379; validation dataset, n = 131; testing dataset, n = 40). Key radiomics features extracted from chest CT images were selected to build a radiomics signature using least absolute shrinkage and selection operator (LASSO) regression. Clinical and clinico-radiomics combined models were constructed. The combined model was further validated in the viral pneumonia cohort, and compared with performance of two radiologists using CO-RADS. The diagnostic performance was assessed by receiver operating characteristics curve (ROC) analysis, calibration curve, and decision curve analysis (DCA). RESULTS: Eight radiomics features and 5 clinical variables were selected to construct the combined radiomics model, which outperformed the clinical model in diagnosing COVID-19 pneumonia with an area under the ROC (AUC) of 0.98 and good calibration in the validation cohort. The combined model also performed better in distinguishing COVID-19 from other viral pneumonia with an AUC of 0.93 compared with 0.75 (P = 0.03) for clinical model, and 0.69 (P = 0.008) or 0.82 (P = 0.15) for two trained radiologists using CO-RADS. The sensitivity and specificity of the combined model can be achieved to 0.85 and 0.90. The DCA confirmed the clinical utility of the combined model. An easy-to-use open-source diagnostic tool was developed using the combined model. CONCLUSIONS: The combined radiomics model outperformed clinical model and CO-RADS for diagnosing COVID-19 pneumonia, which can facilitate more rapid and accurate detection.


Asunto(s)
/métodos , /diagnóstico , Neumonía Viral/diagnóstico por imagen , Neumonía Viral/diagnóstico , Tomografía Computarizada por Rayos X/métodos , Adulto , Anciano , /estadística & datos numéricos , China/epidemiología , Femenino , Ensayos Analíticos de Alto Rendimiento/métodos , Ensayos Analíticos de Alto Rendimiento/estadística & datos numéricos , Humanos , Aprendizaje Automático , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Nomogramas , Pandemias , Neumonía Viral/epidemiología , Interpretación de Imagen Radiográfica Asistida por Computador/métodos , Interpretación de Imagen Radiográfica Asistida por Computador/estadística & datos numéricos , Estudios Retrospectivos , Sensibilidad y Especificidad , Tomografía Computarizada por Rayos X/estadística & datos numéricos , Investigación en Medicina Traslacional
15.
Health Res Policy Syst ; 19(1): 7, 2021 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-33461592

RESUMEN

BACKGROUND: The Collaboration for Evidence-based Healthcare and Public Health in Africa (CEBHA+) is a research consortium concerned with the prevention, diagnosis and treatment of non-communicable diseases. CEBHA+ seeks to engage policymakers and practitioners throughout the research process in order to build lasting relationships, enhance evidence uptake, and create long-term capacity among partner institutions in Ethiopia, Malawi, Rwanda, South Africa and Uganda in collaboration with two German universities. This integrated knowledge translation (IKT) approach includes the formal development, implementation and evaluation of country specific IKT strategies. METHODS: We have conceptualised the CEBHA+ IKT approach as a complex intervention in a complex system. We will employ a comparative case study (CCS) design and mixed methods to facilitate an in-depth evaluation. We will use quantitative surveys, qualitative interviews, quarterly updates, and a policy document analysis to capture the process and outcomes of IKT across the African CEBHA+ partner sites. We will conduct an early stage (early 2020) and a late-stage evaluation (early 2022), triangulate the data collected with various methods at each site and subsequently compare our findings across the five sites. DISCUSSION: Evaluating a complex intervention such as the CEBHA+ IKT approach is complicated, even more so when undertaken across five diverse countries. Despite conceptual, methodological and practical challenges, our comparative case study addresses important evidence gaps: While involving decision-makers in the research process is gaining traction worldwide, we still know very little regarding (i) whether this approach really makes a difference to evidence uptake, (ii) the mechanisms that make IKT successful, and (iii) relevant differences across socio-cultural contexts. The evaluation described here is intended to provide relevant insights on all of these aspects, notably in countries in Sub-Saharan Africa, and is expected to contribute to the science of IKT overall.


Asunto(s)
Enfermedades no Transmisibles/prevención & control , Proyectos de Investigación , Investigación en Medicina Traslacional , África , Prestación de Atención de Salud , Alemania , Investigación sobre Servicios de Salud , Humanos , Estudios Multicéntricos como Asunto , Salud Pública
16.
Int J Mol Sci ; 22(2)2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33467541

RESUMEN

This study aims to provide guidelines to design and perform a robust and reliable physical-chemical characterization of liposome-based nanomaterials, and to support method development with a specific focus on their inflammation-inducing potential. Out of eight differently functionalized liposomes selected as "case-studies", three passed the physical-chemical characterization ( in terms of size-distribution, homogeneity and stability) and the screening for bacterial contamination (sterility and apyrogenicity). Although all three were non-cytotoxic when tested in vitro, they showed a different capacity to activate human blood cells. HSPC/CHOL-coated liposomes elicited the production of several inflammation-related cytokines, while DPPC/CHOL- or DSPC/CHOL-functionalized liposomes did not. This work underlines the need for accurate characterization at multiple levels and the use of reliable in vitro methods, in order to obtain a realistic assessment of liposome-induced human inflammatory response, as a fundamental requirement of nanosafety regulations.


Asunto(s)
Citocinas/inmunología , Inmunidad Innata/inmunología , Mediadores de Inflamación/inmunología , Liposomas/inmunología , Nanoestructuras/química , Investigación en Medicina Traslacional/métodos , 1,2-Dipalmitoilfosfatidilcolina/química , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Colesterol/química , Citocinas/metabolismo , Células Hep G2 , Humanos , Mediadores de Inflamación/metabolismo , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Liposomas/química , Liposomas/farmacología , Tamaño de la Partícula , Fosfatidilcolinas/química
17.
Br J Anaesth ; 126(3): 652-664, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33483132

RESUMEN

BACKGROUND: Immunosuppression after surgery is associated with postoperative complications, mediated in part by catecholamines that exert anti-inflammatory effects via the ß-adrenergic receptor. Phenylephrine, generally regarded as a selective α-adrenergic agonist, is frequently used to treat perioperative hypotension. However, phenylephrine may impair host defence through ß-adrenergic affinity. METHODS: Human leukocytes were stimulated with lipopolysaccharide (LPS) in the presence or absence of phenylephrine and α- and ß-adrenergic antagonists. C57BL/6J male mice received continuous infusion of phenylephrine (30-50 µg kg-1 min-1 i.v.) or saline via micro-osmotic pumps, before LPS administration (5 mg kg-1 i.v.) or caecal ligation and puncture (CLP). Twenty healthy males were randomised to a 5 h infusion of phenylephrine (0.5 µg kg-1 min-1) or saline before receiving LPS (2 ng kg-1 i.v.). RESULTS: In vitro, phenylephrine enhanced LPS-induced production of the anti-inflammatory cytokine interleukin (IL)-10 (maximum augmentation of 93%) while attenuating the release of pro-inflammatory mediators. These effects were reversed by pre-incubation with ß-antagonists, but not α-antagonists. Plasma IL-10 levels were higher in LPS-challenged mice infused with phenylephrine, whereas pro-inflammatory mediators were reduced. Phenylephrine infusion increased bacterial counts after CLP in peritoneal fluid (+42%, P=0.0069), spleen (+59%, P=0.04), and liver (+35%, P=0.09). In healthy volunteers, phenylephrine enhanced the LPS-induced IL-10 response (+76%, P=0.0008) while attenuating plasma concentrations of pro-inflammatory mediators including IL-8 (-15%, P=0.03). CONCLUSIONS: Phenylephrine exerts potent anti-inflammatory effects, possibly involving the ß-adrenoreceptor. Phenylephrine promotes bacterial outgrowth after surgical peritonitis. Phenylephrine may therefore compromise host defence in surgical patients and increase susceptibility towards infection. CLINICAL TRIAL REGISTRATION: NCT02675868 (Clinicaltrials.gov).


Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 1/farmacología , Interacciones Microbiota-Huesped/efectos de los fármacos , Tolerancia Inmunológica/efectos de los fármacos , Leucocitos/efectos de los fármacos , Peritonitis/inmunología , Fenilefrina/farmacología , Complicaciones Posoperatorias/inmunología , Antagonistas Adrenérgicos beta/farmacología , Animales , Células Cultivadas , Citocinas/sangre , Humanos , Laboratorios , Leucocitos/inmunología , Lipopolisacáridos/toxicidad , Masculino , Ratones , Ratones Endogámicos C57BL , Peritonitis/metabolismo , Fenilefrina/administración & dosificación , Complicaciones Posoperatorias/metabolismo , Investigación en Medicina Traslacional
18.
J Transl Med ; 19(1): 32, 2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-33413422

RESUMEN

BACKGROUND: Although it is becoming evident that individual's immune system has a decisive influence on SARS-CoV-2 disease progression, pathogenesis is largely unknown. In this study, we aimed to profile the host transcriptome of COVID-19 patients from nasopharyngeal samples along with virus genomic features isolated from respective host, and a comparative analyses of differential host responses in various SARS-CoV-2 infection systems. RESULTS: Unique and rare missense mutations in 3C-like protease observed in all of our reported isolates. Functional enrichment analyses exhibited that the host induced responses are mediated by innate immunity, interferon, and cytokine stimulation. Surprisingly, induction of apoptosis, phagosome, antigen presentation, hypoxia response was lacking within these patients. Upregulation of immune and cytokine signaling genes such as CCL4, TNFA, IL6, IL1A, CCL2, CXCL2, IFN, and CCR1 were observed in lungs. Lungs lacked the overexpression of ACE2 as suspected, however, high ACE2 but low DPP4 expression was observed in nasopharyngeal cells. Interestingly, directly or indirectly, viral proteins specially non-structural protein mediated overexpression of integrins such as ITGAV, ITGA6, ITGB7, ITGB3, ITGA2B, ITGA5, ITGA6, ITGA9, ITGA4, ITGAE, and ITGA8 in lungs compared to nasopharyngeal samples suggesting the possible way of enhanced invasion. Furthermore, we found comparatively highly expressed transcription factors such as CBP, CEBP, NFAT, ATF3, GATA6, HDAC2, TCF12 which have pivotal roles in lung injury. CONCLUSIONS: Even though this study incorporates a limited number of cases, our data will provide valuable insights in developing potential studies to elucidate the differential host responses on the viral pathogenesis in COVID-19, and incorporation of further data will enrich the search of an effective therapeutics.


Asunto(s)
/genética , Interacciones Microbiota-Huesped/genética , Interacciones Microbiota-Huesped/inmunología , /inmunología , Adulto , Anciano de 80 o más Años , /genética , Citocinas/genética , Femenino , Variación Genética , Humanos , Inmunidad Innata/genética , Integrinas/genética , Pulmón/inmunología , Masculino , Persona de Mediana Edad , Modelos Inmunológicos , Mutación Missense , Nasofaringe/inmunología , Nasofaringe/virología , Pandemias , RNA-Seq , Transducción de Señal/genética , Transducción de Señal/inmunología , Transcriptoma , Investigación en Medicina Traslacional
19.
Health Res Policy Syst ; 19(1): 10, 2021 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-33478499

RESUMEN

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has spread throughout more than 160 countries, infecting millions of people worldwide. To address this health emergency, countries have organized the flow of production and innovation to reduce the impact on health. This article shows the response of the Brazilian scientific community to meet the urgent needs of the public unified health system [SUS], aiming to guarantee universal access to an estimated population of 211 million. By December 2020, Brazil had recorded more than six million cases and approximately 175,000 deaths. METHODS: We collected data on research, development and innovation projects carried out by 114 public universities (plus Oswaldo Cruz Foundation [Fiocruz] and Butantan Institute), as reported on their websites. Additionally, we examined the studies on COVID-19 approved by the National Comission for Research Ethics, as well as those reported on the Ministry of Education website as of May 15, 2020. RESULTS: The 789 identified projects were classified according to research categories as follows: development and innovation (n = 280), other types of projects (n = 226), epidemiologic research (n = 211), and basic research on disease mechanisms (n = 72). Most proposals focused on the development and innovation of personal protective equipment, medical devices, diagnostic tests, medicines and vaccines, which were rapidly identified as research priorities by the scientific community. Some promising results have been observed from phase III vaccine trials, one of which is conducted in partnership with Oxford University and another of which is performed with Sinovac Biotech. Both trials involve thousands of volunteers in their Brazilian arms and include technology transfer agreements with Fiocruz and the Butantan Institute, respectively. These vaccines proved to be safe and effective and were immediately licensed for emergency use. The provision of doses for the public health system, and vaccination, started on January 17, 2021. CONCLUSIONS: The mobilized Brazilian scientific community has generated comprehensive research, development and innovation proposals to meet the most urgent needs. It is important to emphasize that this response was only possible due to decades of investment in research, development and innovation in Brazil. We need to reinforce and protect the Brazilian science, technology and innovation system from austerity policies that disregard health and knowledge as crucial investments for Brazilian society, in line with the constitutional right of universal health access and universal health coverage.


Asunto(s)
Investigación Biomédica , Prestación de Atención de Salud , Pandemias , Salud Pública , Investigación Biomédica/economía , Brasil/epidemiología , Economía , Urgencias Médicas , Humanos , Industrias , Apoyo a la Investigación como Asunto , Investigación en Medicina Traslacional , Universidades , Vacunación , Vacunas
20.
Med Hypotheses ; 146: 110473, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33385879

RESUMEN

Severe forms of the Coronavirus disease 2019 (COVID-19) are characterized by an enhanced inflammatory syndrome called "cytokine storm" that produces an aberrant release of high amounts of cytokines, chemokines, and other proinflammatory mediators. The pathogenetic role of the "cytokine storm" has been confirmed by the efficacy of immunosuppressive drugs such as corticosteroids along with antiviral drugs in the treatment of the severe forms of this disease. Phenylmethimazole (C10) is a derivative of methimazole with anti-inflammatory properties. Studies performed both in vitro and in vivo have shown that C10 is able to block the production of multiple cytokines, chemokines, and other proinflammatory molecules involved in the pathogenesis of inflammation. Particularly, C10 is effective in reducing the increased secretion of cytokines in animal models of endotoxic shock. We hypothesize that these effects are not limited to the endotoxic shock, but can also be applied to any disease characterized by the presence of a "cytokine storm". Therefore, C10 may be a potential drug to be used alternatively or in association with the corticosteroids or other immunosuppressive agents in the severe forms of COVID-19 as well as other viral diseases that induce a "cytokine storm". Preclinical and clinical studies have to be performed to confirm this hypothesis.


Asunto(s)
/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Metimazol/análogos & derivados , Tionas/farmacología , Animales , Antiinflamatorios/farmacología , Antivirales/farmacología , Síndrome de Liberación de Citoquinas/inmunología , Citocinas/antagonistas & inhibidores , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Metimazol/farmacología , Ratones , Pandemias , Choque Séptico/tratamiento farmacológico , Choque Séptico/inmunología , Investigación en Medicina Traslacional
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